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Attentional bias towards and away from fearful faces is modulated by developmental amygdala damage
Morteza Pishnamazi, Abbas Tafakhori, Sogol Loloee, Amirhossein Modabbernia, Vajiheh Aghamollaii, Bahador Bahrami, Joel S. Winston
PII: DOI:
S0010-9452(16)30077-6 10.1016/j.cortex.2016.04.012
Reference: CORTEX 1729
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Cortex
14 August 2015 19 January 2016 10 April 2016
Please cite this article as: Pishnamazi M, Tafakhori A, Loloee S, Modabbernia A, Aghamollaii V, Bahrami B, Winston JS, Attentional bias towards and away from fearful faces is modulated by developmental amygdala damage, CORTEX (2016), doi: 10.1016/j.cortex.2016.04.012.
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Title:
Attentional bias towards and away from fearful faces is modulated by developmental amygdala damage
Author list:
Morteza Pishnamazi a,b, Abbas Tafakhori a*, Sogol Loloee a, Amirhossein Modabbernia a,c, Vajiheh Aghamollaii d, Bahador Bahrami e A, Joel S Winston ef A
Affiliations:
a Iranian Center of Neurological Research, Department of Neurology, Imam Khomeini Hospital, Tehran University of Medical Sciences, Tehran, Iran.
b Students' Scientific Research Center, Tehran University of Medical Sciences, Tehran, Iran.
c Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, USA.
d Roozbeh Psychiatric Hospital, Tehran University of Medical Sciences, Tehran, Iran.
e UCL Institute of Cognitive Neuroscience, University College London, London, United Kingdom.
f Wellcome Trust Centre for Imaging Neuroscience, University College London, London, United Kingdom.
A These authors contributed equally to this work.
* Corresponding author:
Dr Abbas Tafakhori
Department of Neurology, Imam Khomeini Hospital, Tehran University of Medical Sciences, Tehran, Iran. P.O. Box, 1419733141 Tel.: +98 21 66948899; Fax: +98 21 66581558 Email: Abbas Tafakhori; abbas.tafakhori@gmail.com Morteza Pishnamazi; m.pishnamazi@gmail.com
Keywords:
Amygdala; Spatial attention; Urbach-Wiethe Disease; Dot-probe; Emotional processing Word count:
Abstract: 241 words; Article body text: 4347 words (excluding abstract, acknowledgments, financial
disclosure, references, and figure legends)
Figures: 4 (four); Tables: 0 (zero); Supplementary Data: 2 (two)
1 Abstract
2 The amygdala is believed to play a major role in orienting attention towards threat-related stimuli.
3 However, behavioral studies on amygdala-damaged patients have given inconsistent results—variously
4 reporting decreased, persisted, and increased attention towards threat. Here we aimed to characterize the
5 impact of developmental amygdala damage on emotion perception and the nature and time-course of
6 spatial attentional bias towards fearful faces. We investigated SF, a 14-year-old with selective bilateral
7 amygdala damage due to Urbach-Wiethe disease, and ten healthy controls. Participants completed a fear
8 sensitivity questionnaire, facial expression classification task, and dot-probe task with fearful or neutral
9 faces for spatial cueing. Three cue durations were used to assess the time-course of attentional bias. SF
10 expressed significantly lower fear sensitivity, and showed a selective impairment in classifying fearful
11 facial expressions. Despite this impairment in fear recognition, very brief (100ms) fearful cues could
12 orient SF's spatial attention. In healthy controls, the attentional bias emerged later and persisted longer.
13 SF's attentional bias was due solely to facilitated engagement to fear, while controls showed the typical
14 phenomenon of difficulty in disengaging from fear. Our study is the first to demonstrate the separable
15 effects of amygdala damage on engagement and disengagement of spatial attention. The findings indicate
16 that multiple mechanisms contribute in biasing attention towards fear, which vary in their timing and
17 dependence on amygdala integrity. It seems that the amygdala is not essential for rapid attention to
18 emotion, but probably has a role in assessment of biological relevance.
19 1. Introduction
20 Evolutionary pressure ensures that in systems with limited perceptual capacity, stimuli that indicate
21 potential environmental dangers receive privileged access to resources (Dolan, 2002; Ohman & Mineka,
22 2001). Numerous studies show that attention is preferentially oriented towards and maintained for longer
23 by threat-related items (Yiend, 2010). Such attentional bias has been documented using a variety of
24 stimuli (e.g. facial expressions, words, scenes) (Yiend, 2010) and evidence shows that threat-related
25 stimuli affect both engagement and disengagement components of attention (Cisler, Bacon, & Williams,
26 2009; Koster, Crombez, Van Damme, Verschuere, & De Houwer, 2004; Yiend, 2010). Attentional biases
27 are observed at time-scales encompassing both automatic and strategic stages of information processing
28 (Cisler et al., 2009; Cisler & Koster, 2010; Koster, Verschuere, Crombez, & Van Damme, 2005).
29 Abnormal attention orienting to threat is a characteristic feature of anxiety disorders (Cisler & Koster,
30 2010; Salum et al., 2013; Shechner et al., 2012) and attentional bias modification has a role in anxiety
31 treatment (Hakamata et al., 2010). However, the precise neural mechanisms that underlie attentional bias
32 towards threat-related stimuli remain unclear.
33 The current literature on the neural mechanisms of attention to threat presumes a pivotal role for the
34 amygdala (Pourtois, Schettino, & Vuilleumier, 2013). It is argued that the amygdala's bidirectional
35 connections with sensory areas enhance perceptual processing of emotional stimuli (Freese & Amaral,
36 2009; LeDoux, 2007; Vuilleumier, 2005) and amygdala is therefore responsible for early ("automatic")
37 facilitated engagement of attention to threat (Cisler & Koster, 2010; Vuilleumier, 2005). Findings suggest
38 that the later strategic stages of attention to threat and the disengagement component of attentional bias
39 are controlled by higher-order cortical networks, predominantly the prefrontal attentional network (Cisler
40 & Koster, 2010; Pourtois et al., 2013). Neuroimaging studies show that the enhanced cortical activations
41 in response to fearful faces are absent in amygdala-damaged patients (Rotshtein et al., 2010; Vuilleumier,
42 Richardson, Armony, Driver, & Dolan, 2004) and support the role of amygdala in threat-related attention.
43 However the causal involvement of amygdala in biasing attention to emotion has not been confirmed
44 (Pessoa & Adolphs, 2010). The handful of behavioral experiments on amygdala-damaged patients have
45 given inconsistent results. Out of seven published studies (Anderson & Phelps, 2001; Bach, Hurlemann,
46 & Dolan, 2015; Bach, Talmi, Hurlemann, Patin, & Dolan, 2011; Piech et al., 2010, 2011; Terburg et al.,
47 2012; Tsuchiya, Moradi, Felsen, Yamazaki, & Adolphs, 2009), only two provide positive evidence for
48 impaired attention to threat after amygdala damage (Anderson & Phelps, 2001; Bach et al., 2015). In an
49 early influential study, Anderson and Phelps (2001) showed that a patient with non-selective bilateral
50 temporal lobe lesions did not exhibit facilitated attention to aversive words during the attentional blink
51 task. However, testing the same task on two patients with focal amygdala lesions failed to replicate this
52 effect (Bach et al., 2011). Two other experiments, one using attentional blink with pictures (Piech et al.,
53 2011) and the other using continuous flash suppression paradigm (Tsuchiya et al., 2009, experiment 3)
54 also report that threat-related attentional bias persists despite amygdala damage. Another piece of positive
55 evidence comes from a visual search paradigm that showed impaired attention to angry faces after
56 amygdala damage (Bach et al., 2015). However, two other studies that employed visual search with fear-
57 related targets did not find any deficit in similar patients (Piech et al., 2010; Tsuchiya et al., 2009,
58 experiment 2). Adding to the disparity within the literature, there is one report of increased attention to
59 fear in five patients with lesions relatively selective to basolateral amygdala (Terburg et al., 2012). These
60 inconsistencies warrant further investigations to explain the exact role of amygdala in triggering and
61 maintaining the attentional bias towards threat. Particularly, what is lacking is a clear characterization of
62 behavioral consequences of amygdala damage based upon the components of attentional bias and the
63 stages of information processing (Cisler & Koster, 2010; Pourtois et al., 2013).
64 In the current study, we aim to characterize emotion perception and the temporal dynamics of spatial
65 orienting towards fearful faces in an adolescent patient with selective bilateral amygdala damage due to
66 Urbach-Wiethe disease (UWD) compared to a N=10 healthy controls. UWD is a rare genetic condition
67 that causes focal symmetrical calcifications in amygdala bilaterally with sparing of other brain regions
68 (Appenzeller et al., 2006). Several previous cases of children and adolescents with bilateral amygdala
69 damage have been reported (Emsley & Paster, 1985; Ito et al., 2000; Omrani et al., 2012; Savage,
70 Crockett, & McCabe, 1988). However, very little information could be found on the cognitive
71 consequences of amygdala damage at young ages. In particular, the attentional bias to threat has been
72 solely investigated in adult amygdala-damaged patients and few neuropsychological assessments of
73 adolescent patients have mainly focused on deficits in emotion recognition and memory (Steenberg, 2014;
74 Thornton et al., 2008). Attentional bias to threat begins very early in life (Creswell et al., 2008; LoBue &
75 DeLoache, 2010) and is consistently observed across age groups (preschoolers: LoBue, 2009; preteens:
76 Waters, Lipp, & Spence, 2004; and adolescents: Wolters et al., 2012). Threat bias appears to be present in
77 early childhood as a core function that facilitates survival and adaptive social behavior (LoBue &
78 Rakison, 2013), but biases then change as a function of development (Field & Lester, 2010). With
79 increasing age, moderating factors such as trait anxiety, past experiences and environmental events seem
80 to have a larger effect on the strength and direction of attentional biases (Field & Lester, 2010; Shechner
81 et al., 2012). However, the neural mechanisms underlying attention to threat seem not to change during
82 development (Lindstrom et al., 2009).
83 We first explored the emotional experience of our patient using a fear sensitivity questionnaire and a
84 facial expression classification task. Next, to test the spatial orientation of attention, we adopted the 'dot-
85 probe' double cuing task (MacLeod, Mathews, & Tata, 1986). This task allows drawing inferences about
86 the engagement and disengagement of attention (Koster, Crombez, Verschuere, & De Houwer, 2004) and
87 can illuminate both automatic and strategic stages of attentional bias by employing short and long cue
88 exposure durations (Koster et al., 2005). In the dot-probe task, targets are presented either at the same or
89 opposite to the location of a preceding emotionally salient cue. The difference in reaction time (RT) to
90 targets located at congruent vs. incongruent location relative to the cue is interpreted as the bias of spatial
91 attention (i.e., 'vigilance' or 'avoidance'). We employed the dot-probe task with face-pair cues that could
92 both be neutral (baseline) or comprise a neutral and fearful face. We used three cue exposure durations
93 (100, 500, 1000ms) to examine the time-course of attentional bias. Assuming that the amygdala's
94 contribution in directing attention is more critical at early stages of information processing, we expected
95 to find disparate impacts of amygdala damage on attentional bias at short versus late time-points.
96 2. Materials and Methods
2.1. Participants
Patient SF (female, 14.5 years old at the time of testing) was diagnosed with UWD after investigations
99 for epilepsy showed bilateral amygdala lesions (Omrani et al., 2012) (Fig. 1). She had a 10-year history of
100 focal seizures but had been drug- and symptom-free for 8 months when tested. Psychiatric evaluation of
101 SF did not converge to any diagnosis but revealed histories of two interpersonal traumatic events, three
102 and four years ago, and a history of suicidal ideations, with a plan as recently as a month prior to the
103 study (for more details see Supplementary Material, §1). Ten female participants, matched for gender
104 (female), handedness (right handed), age (M ± SD=14.8 ± 0.2), education (8.5 years of formal schooling),
105 home language (Persian), and socioeconomic level, were recruited as control subjects. A physician
106 interviewed the control group to confirm psychiatric and neurologic health. To measure everyday fear
107 sensitivity, SF and control participants completed the Fear Survey Schedule for Children-Revised (FSSC-
108 R) (Ollendick, 1983). The Ethics Committee at the Tehran University of Medical Sciences approved all
109 procedures and informed consent was obtained from all participants.
110 2.2. Facial expression classification
111 Color face images from Radboud Face Database (RaFD) (Langner et al., 2010) were employed. A set
112 of 234 images (39 Identities (19 females) x 6 Expressions:
113 'happy'/'sad'/'fearful'/'angry'/'surprised'/'disgusted') were presented in random order. On each trial one
114 image was displayed on a black background with all the adjectives (in Persian) displayed alongside on the
115 right. Participants selected the best-fitting label by mouse, with no time limit.
116 2.3. Emotional dot-probe task
117 A subset of RaFD images (27 models; 12 female; fearful and neutral expressions) were used. Faces
118 were grayscale-transformed, equalized for intensity and contrast, and cropped to eliminate hair and other
119 features falling outside the oval borders (6° main diagonal).
120 Each trial (Fig. 2.A) started with a central black fixation cross (0.2° * 0.2°, 5 cd/m2; duration 1000ms)
121 on a uniform gray background (15 cd/m2). Subsequently, two face stimuli (same identity) were presented
122 at 7° eccentricity to the left and right of fixation. To probe the time-course of attentional effects, three cue
123 durations (100, 500, or 1000ms) were used. On disappearing, the cue was replaced immediately by the
124 target stimulus. The target was a circle or square (0.5° * 0.5°; dark-gray, 10 cd/m2) that appeared in the
125 left or right visual field (LVF, RVF) at 7° eccentricity with equal probability, and participants were
126 instructed to maintain central fixation and report the target's shape by pressing the designated keyboard
127 buttons. Accuracy and speed were equally emphasized.
128 We tested three conditions: 'congruent', 'incongruent', and 'neutral'. On neutral trials, the same face
129 with a neutral expression was displayed on both sides. In the other two conditions, one of the two faces
130 was fearful. In congruent trials (Fig. 2.A; left), the target appeared on the same side as the fearful face. In
131 incongruent trials (Fig. 2.A; middle) the target appeared on the opposite hemifield. In total each
132 participant completed 1440 trials over two testing sessions, each lasting approximately 40 minutes. Each
133 configuration (Cue duration * Trial type) occurred with equal probability in random order.
134 Based on previous studies (Mogg & Bradley, 1998), we reasoned that a positive congruency effect
135 [RTcongruent<RTincongruent] would indicate 'vigilance' to fear whereas the reverse effect would indicate fear
136 'avoidance'. Comparison with a baseline condition (without emotional cueing) is necessary to determine
137 the components of attentional bias (i.e., 'engagement' or 'disengagement') (Koster, Crombez,
138 Verschuere, et al., 2004). A positive congruency effect could be either due to 'facilitated engagement'
139 [RTcongruent<RTneutral] (Fig. 2.B; left) or 'difficulty in disengagement' [RTincongruent >RTneutral] (Fig. 2.B;
140 middle).
141 2.4. Statistical considerations
142 Analysis of single-case experiments requires special statistical methods (McIntosh & Brooks, 2011).
143 We employed the modified t test proposed by Crawford and Howell (1998) to test the significance of the
144 deficits in SF's fear sensitivity score and expression classification performance. This procedure is
145 particularly suited for comparing a single observation with the mean of a small control group (Crawford
146 & Garthwaite, 2006, 2012). The logic behind Crawford & Howell's method can be extended to analysis
147 of variance (ANOVA) procedure (Corballis, 2009b), and is valid for factorial analysis of scores measured
148 under several conditions of the same task (Corballis, 2009a; Crawford, Garthwaite, & Howell, 2009). See
149 Supplementary Material (§5) for further details and discussion of alternative statistical methods. We
150 applied ANOVA on mean reaction times of subjects to test for main effects and interactions between
151 conditions of the dot-probe experiment. For pairwise comparison between mean reaction times of SF in
152 each trial type (congruent, incongruent, neutral) we used the Crawford and Garthwaite's revised test for
153 difference (Crawford & Garthwaite, 2005). This method is a modified paired-sample t test suited for
154 comparing a patient's performance on parallel versions of a task with that of controls under two different
155 experimental conditions. Corresponding pairwise comparisons for control subjects were run using
156 conventional paired t tests. For confirmation, we reanalyzed SF's dot-probe data using trial-by-trial
157 reaction times (i.e., not averaged over conditions) and conventional statistical methods (Supplementary
158 Material, §6). IBM SPSS Statistics (Ver. 20.0) was used for data analysis. In SPSS software, the
159 Crawford and colleagues methods are applied by defining the single case as a group of N = 1 and no
160 further adjustment is required (Corballis, 2009a). In all tests ^-values<0.05 were considered significant
161 (with Bonferroni adjustment where appropriate).
162 3. Results
3.1. Fear sensitivity The FSSC-R questionnaire lists 80 specific situations or objects (e.g. "getting lost in a strange place",
165 "snakes", etc.). Participants described how much they fear each item ("none"/"some"/"a lot"; scored 1-3
166 respectively). SF scored 98, reporting "a lot" of fear for only three items (see Supplementary Material,
167 §1), while controls' scored significantly higher (M±5D=142±14.8; range: 119-168; t(9)=2.80;p=0.02)
168 (Fig. 3.A).
169 3.2. Facial expression classification
170 With the exception of fearful expressions, SF and controls were equally accurate (all p>0.05) in
171 identifying the relevant emotional label for the faces (Fig. 3.B). When a fearful face was presented, SF
172 chose the correct label in only 18% of trials, significantly lower than the average performance of controls
173 [72%; t(9)=3.85; p=0.004]. SF categorized fearful faces as 'surprised' in 69% of trials; whereas controls
174 had a broader distribution of errors (Fig. 3.C).
175 3.3. Emotional dot-probe task
176 Errors in reporting the shape of the target were rare. On average, controls made an error on 0.9% of
177 trials (SD=0.8). SF had a significantly higher error rate [3.1%; t(9)=2.53;p=0.032]. Prior to averaging
178 RTs, error trials and trials with outlier RTs were excluded. Outliers were defined separately for each
179 participant as RTs that deviated more than 1.5 inter-quartile ranges from the upper and lower quartiles.
180 These trials comprised 4.2% of SF's data and 2.5% of all collected data. We found no evidence for speed-
181 accuracy trade-off (see Supplementary Material, §4).
182 Mean RTs for each experimental condition (Supplementary Table 1) were entered into a 3-way
183 repeated measures ANOVA with Group (controls/SF) * Cue duration (100/500/1000ms) * Congruency
184 (congruent/incongruent) as factors. None of the main effects nor the 2-way interactions were significant.
185 However, a significant 3-way interaction [F(2, 18)=9.77; p=0.001] showed that the temporal pattern of
186 emotion-attention interaction differed between SF and controls. In follow-up tests, the Cue duration *
187 Congruency interaction was examined within SF and the control group separately and showed temporal
188 mediation of attentional effects in both SF [F(2, 18)=5.42; p=0.014] and controls [F(2, 18)=9.89;
189 p=0.001]. Note that in this analysis the RT from neutral trials are not included as they cannot be
190 differentiated as being congruent or incongruent. Attentional bias scores [RTcongruent-RTincongruent] for SF
191 and controls at each cue duration are presented in Figure 4.A. As mentioned earlier, comparison with
192 neutral trials' RT (i.e. baseline RT unaffected by attentional cueing) is necessary to determine which
193 component of spatial attention is affected (Koster, Crombez, Verschuere, et al., 2004). To reveal the
194 attentional behavior of SF and controls at each cue duration, we performed pairwise comparisons between
195 all the three trial types. Including the baseline condition tripled the number of planned tests. We used
196 Bonferroni adjustment to control the probability of false positives.
197 3.3.1. SF
198 With the shortest cue duration (100ms), SF showed a positive congruency effect [t(9)=3.31; p=0.027]
199 implying rapid vigilance for fear. This attentional bias disappeared with longer cue durations [500ms:
200 t(9)=0.78; p>0.l; 1000ms t(9)=2.06; p>0.1]. Pairwise comparison with baseline confirmed that at cue
201 durations of 100ms, SF showed facilitated engagement to fear location (RTcongruent<RTneutral [t(9)=2.96;
202 p=0.048]; no significant difference between RTincongruent and RTneutral [t(9)=0]) (Fig. 4.B). When cue
203 duration was 500ms, there was no bias but compared to the neutral condition, SF responded more slowly
204 in the emotional trials with significantly longer RTs in both congruent [t(9)=4.51; p=0.004] and
205 incongruent [t(9)=3.16; p=0.035] trials (Fig. 4.C). With the longest cue duration (1000ms), the
206 congruency effect was not statistically significant. Comparison with the neutral condition showed a
207 significant delay in responding to congruent trials [t(9)=2.96; p=0.048] but not incongruent trials
208 [t(9)=0.11] (Fig. 4.D).
209 3.3.2. Controls
210 With the shortest cue duration (100ms), controls showed a marginal effect of fear avoidance
211 [t(9)=2.87; p=0.056]. Longer cue durations resulted in significant attentional bias towards fear at both
212 500ms [t(9)=3.20; p=0.032] and 1000ms [t(9)=3.00; p=0.045] conditions. Comparison with baseline
213 revealed a trend for longer RTs in congruent trials in the 100ms condition [t(9)=2.79; p=0.064] (Fig. 4.E).
214 At cue durations of 500ms there was no significant difference between either congruent or incongruent
215 conditions and the baseline (Fig. 4.F). At cue durations of 1000ms the mean RT in incongruent trials was
216 significantly longer than neutral baseline [t(9)=3.77; p=0.013] suggesting that controls had difficulty in
217 disengaging fear location (Fig. 4.G).
218 4. Discussion
219 We investigated SF, a 14-year-old female with bilateral amygdala lesions due to UWD, and ten
220 matched controls. Psychiatric evaluation of SF revealed no pathological diagnosis. The fear survey
221 revealed her significantly lower fear sensitivity. These findings are consistent with prior reports from an
222 adult UWD patient (Feinstein, Adolphs, Damasio, & Tranel, 2011; Tranel, Gullickson, Koch, & Adolphs,
223 2006). Moreover we found that SF is specifically impaired in classifying the fearful facial expressions, a
224 frequent finding after the damage of amygdala either due to UWD (Adolphs, Tranel, Damasio, &
225 Damasio, 1994; Becker et al., 2012; Siebert, Markowitsch, & Bartel, 2003) or other less selective
226 pathologies (Schmolck & Squire, 2001; Sprengelmeyer et al., 1999).
227 Our main aim was to investigate the causal contribution of amygdala to the orienting of spatial
228 attention by fearful faces. We measured attentional bias using a dot-probe task with congruent and
229 incongruent cues and used various cue durations to investigate the temporal dynamics of attentional
230 biases. To discriminate between engagement and disengagement components of attention, we included
231 trials with neutral/neutral face pairs to measure baseline RTs. The results revealed that SF and controls
232 demonstrated opposite patterns of attentional biases in the early and late time-points after attentional cue
233 onset (Fig. 4.A). SF showed attentional bias towards fear at the shortest tested cue duration of 100ms. In
234 controls, the attentional bias towards fearful faces was observed in the middle and longer time windows
235 (5 00-1000ms post-cue). In contrast, SF showed no bias at the moderate cue durations, and only a weak
236 bias away from the fearful cue location at 1000ms. These findings suggest that SF's attention was rapidly
237 engaged to the fearful face but shortly afterwards her attention disengaged from the fear location (by a
238 timescale of <500ms post-cue) and proceeded to avoid the previously attended location possibly via a
239 mechanism similar to 'inhibition of return ' (Klein, 2000). Healthy subjects, on the other hand, showed
240 difficulty in disengaging attention from the location of fearful faces (Fig. 4.G). Our results reveal for the
241 first time the separable effects of amygdala damage on engagement and disengagement components of
242 spatial attention.
243 We found that the attentional bias in normal subjects was due to difficulty in disengaging attention
244 from the location of fear. SF showed an early bias towards fear due to facilitated engagement of attention,
245 but unlike the control group did not show disengagement cost at any of three measured time-points. This
246 is a peculiar finding because abundant dot-probe data demonstrate that unlike disengagement effects, that
247 might occur independently, facilitated engagement to emotion does not occur alone and is almost always
248 followed by difficulty in disengagement (Cisler & Koster, 2010). Our results thus imply that amygdala
249 damage abolishes the difficulty in disengaging from fear location at moderate to late time points,
250 suggesting that amygdala function is necessary for the disengagement costs to occur. Electrophysiological
251 and neuroimaging studies have begun to fractionate the neural underpinnings of the facilitated capture of
252 spatial attentional by fearful faces and the attentional disengagement costs imposed by such stimuli, and
253 are consistent with the suggestion that these effects have dissociable neural correlates (Pourtois et al.,
254 2005; Pourtois, Schwartz, Seghier, Lazeyras, & Vuilleumier, 2006). Future studies, could test whether
255 these neural mechanisms are causally dependent upon amygdala projections. Our current results imply
256 that amygdala actively increases the attentional dwell time on biologically significant signals.
257 Strikingly, we found rapid engagement of attention by fear in SF at the shortest cue duration. This
258 attentional bias suggests that despite bilateral amygdala damage and impairment of fear recognition,
259 fearful faces could nonetheless rapidly orient SF's spatial attention. Attentional orienting by such short
260 cue durations suggests that a reflexive, bottom-up mechanism is still functional in SF. This is consistent
261 with previous reports that the amygdala is not essential for rapidly detecting and attending to emotional
262 stimuli (Bach et al., 2011; Piech et al., 2010, 2011; Tsuchiya et al., 2009). But assuming no role for the
263 amygdala in orienting attention to emotion is problematic for interpreting multiple studies that showed
264 that projections from the amygdala modulated perceptual and attentional responses to fear-related stimuli
265 (Benuzzi et al., 2004; Rotshtein et al., 2010; Vuilleumier et al., 2004). Damage to amygdala abolishes
266 fear-induced enhancement of early visual responses (Rotshtein et al., 2010) and these early enhancements
267 appear functionally relevant to the attentional bias towards fear in the dot-probe paradigm (Pourtois,
268 Grandjean, Sander, & Vuilleumier, 2004). So what is the function of amygdala-mediated enhancement of
269 visual responses, if amygdala is not necessary for initial attention to fear?
270 Current theories propose that the function of amygdala is not specific to emotional processing, instead
271 playing a role in optimizing the allocation of perceptual resources to stimuli based on biological value and
272 goal relevance (Pessoa & Adolphs, 2010; Sander, Grafman, & Zalla, 2003). From this perspective it is
273 reasonable to think that amygdala might act to either facilitate or prevent orienting towards threat signals,
274 by weighing up the cost of ignoring potential danger against the benefit of goal-directed tasks (Pessoa,
275 2009). Indeed we found that compared to SF, the shift of attention towards fear arose later in healthy
276 controls. A brief task-irrelevant fearful face is a relatively weak signal of environmental danger—and is
277 safe to ignore, as controls did in the 100ms condition of our experiment. However, as the fearful face
278 persists its biological significance increases; at longer cue durations it is sensible to interrupt the task and
279 attend to the fearful face location—and engage with it until the potential source of threat is resolved. The
280 delay shown by healthy control participants in orienting to fear fits this ecological perspective on
281 amygdala function (Pessoa, 2009) and suggests that amygdala can actively act to suppress the fear bias
282 when threat is weak and irrelevant. This claim is supported by at least one other study of several UWD
283 patients which provided causal evidence that the basolateral amygdala nucleus is necessary to inhibit the
284 reflexive distraction of attention by task-irrelevant threat signals (Terburg et al., 2012). Without a
285 functional amygdala, SF showed reflexive attention to brief signals of fear and avoided the long-lasting
286 signals of potential threat. These are both harmful strategies and suggest that she was impaired in
287 adjusting attentional selection based on the biological significance of sensory events. The current set of
288 findings corroborate the notion that amygdala is crucial for top-down guidance of spatial attention to
289 biologically relevant and not necessarily emotional features of the visual scene (Jacobs, Renken, Aleman,
290 & Cornelissen, 2012; Pourtois et al., 2013). Remarkably, the failure in top-down guidance of attention
291 seems to be the basis of impaired recognition of fearful faces, which is the hallmark deficit of amygdala-
292 damaged patients. Studies on SM, the single-most studied UWD case (2008; 2005) suggest that
293 amygdala-damaged patients are not impaired in perception of fear per se, but fail to properly attend to
294 parts of face images that are relevant for correct expression recognition (Kennedy & Adolphs, 2011).
295 Intriguingly, SM's fear recognition deficit was corrected after an explicit instruction to attend to the eye
296 region of faces (Adolphs et al., 2005). Our patient mostly labelled 'fearful' faces as 'surprised' (see Fig
297 3.C). Compared to other expressions, there is more overlap between the facial features that relay fear and
298 surprise emotions (Smith, Cottrell, Gosselin, & Schyns, 2005) and discriminating the two relies on active
299 attentional selection (Schyns, Petro, & Smith, 2009). Therefore, SF's deficit in the facial expression
300 classification task might also be consistent with a role for amygdala in top-down attentional guidance.
301 Here we discussed findings from a single case study. For this reason, caution should be exercised in
302 interpreting the results for amygdala's attentional function based on this study alone. Further studies on
303 patients with bilateral amygdala damage are needed to confirm current results. Several points should be
304 noted in conducting future studies. First, the amygdala is a heterogeneous structure and animal studies
305 have found disparate behavioral outcomes after lesions of specific subnuclei (Swanson & Petrovich,
306 1998). Precise characterization of location and extent of patient's lesions, might help reconcile the reports
307 of diminished (Anderson & Phelps, 2001), preserved (Bach et al., 2011), and even increased attention to
308 fear after amygdala damage (Terburg et al., 2012). Second, here we only used task-irrelevant fearful faces
309 to cue attention. The consequences of amygdala damage on attentional orientation by task-relevant and
310 more potent danger signals remain to be investigated. Third, we relied on changes in RT to study
311 attentional effects. However, threat-signals affect both the latency (Pessoa, Padmala, Kenzer, & Bauer,
312 2012) and accuracy (Phelps, Ling, & Carrasco, 2006) of perceptual responses—occasionally in opposing
313 directions (Bocanegra, 2014). The separable roles of amygdala in mechanisms underlying speed-accuracy
314 trade-offs is an important, yet unstudied topic. Future research should focus on explicit characterization of
315 the time-course, attentional components, and neural pathways that comprise interactions between
316 amygdala and attentional effects (Cisler & Koster, 2010). This seems a promising approach for
317 unravelling amygdala's functions, and it's role in pathophysiology of anxiety disorders (Birn et al., 2014;
318 Milham et al., 2005). Abnormal attentional bias towards threat robustly relates to elevated trait anxiety
319 (Bar-Haim, Lamy, Pergamin, Bakermans-Kranenburg, & van IJzendoorn, 2007; Hakamata et al., 2010),
320 and fUture theories must address such relationships.
321 5. Conclusion
322 We showed that an adolescent patient with bilateral amygdala damage rapidly attended fearful faces,
323 but disengaged from them prematurely. To our knowledge, this is the first demonstration of the separable
324 effects of amygdala damage on engagement and disengagement components of spatial attention. Our
325 findings show that attentional behavior is shaped by multiple influences from amygdala, occurring at
326 distinct time points; and suggest that the amygdala has a modulatory role in threat-related attentional bias.
327 It seems that the amygdala is not essential for rapid attention to emotion. Instead, the amygdala probably
328 has a crucial role in assessing the biological relevance of sensory events, and is essential for efficient
329 allocation of perceptual resources.
330 Acknowledgements
331 The authors would like to thank SF and her family for their cooperation and the Tazkieh High School
332 for assistance in recruiting the control subjects. BB is supported by the European Research Council
333 (Grant No. 309865 NEUROCODEC). JSW is supported by the Wellcome Trust (Grant No. 095939) and
334 the Wellcome Trust Centre for Neuroimaging is supported by core funding from the Wellcome
335 Trust (Grant No. 091593). This work was supported by Tehran University of Medical Sciences (Grant
336 No. 91-01-3017196 to AT).
337 Financial Disclosure
338 The authors report no biomedical financial interests or potential conflicts of interest.
339 References
340 Adolphs, R. (2008). Fear, faces, and the human amygdala. Current Opinion in Neurobiology, 18(2), 166—
341 72. http://doi.Org/10.1016/j.conb.2008.06.006
342 Adolphs, R., Gosselin, F., Buchanan, T. W., Tranel, D., Schyns, P., & Damasio, A. R. (2005). A
343 mechanism for impaired fear recognition after amygdala damage. Nature, 433(7021), 68-72.
344 http://doi.org/10.1038/nature03086
345 Adolphs, R., Tranel, D., Damasio, H., & Damasio, A. (1994). Impaired recognition of emotion in facial
346 expressions following bilateral damage to the human amygdala. Nature, 372(6507), 669-672.
347 http://doi.org/10.1038/372669a0
348 Anderson, A. K., & Phelps, E. a. (2001). Lesions of the human amygdala impair enhanced perception of
349 emotionally salient events. Nature, 411(6835), 305-9. http://doi.org/10.1038/35077083
350 Appenzeller, S., Chaloult, E., Velho, P., de Souza, E. M., Araujo, V. Z., Cendes, F., & Li, L. M. (2006).
351 Amygdalae calcifications associated with disease duration in lipoid proteinosis. Journal of
352 Neuroimaging: Official Journal of the American Society of Neuroimaging, 16(2), 154-6.
353 http://doi.org/10.1111/j.1552-6569.2006.00018.x
354 Bach, D. R., Hurlemann, R., & Dolan, R. J. (2015). Impaired threat prioritisation after selective bilateral
355 amygdala lesions. Cortex; a Journal Devoted to the Study of the Nervous System and Behavior, 63,
356 206-13. http://doi.org/10.1016/j.cortex.2014.08.017
357 Bach, D. R., Talmi, D., Hurlemann, R., Patin, A., & Dolan, R. J. (2011). Automatic relevance detection in
358 the absence of a functional amygdala. Neuropsychologia, 49(5), 1302-5.
359 http://doi.org/10.1016/j.neuropsychologia.2011.02.032
360 Bar-Haim, Y., Lamy, D., Pergamin, L., Bakermans-Kranenburg, M. J., & van IJzendoorn, M. H. (2007).
361 Threat-related attentional bias in anxious and nonanxious individuals: a meta-analytic study.
362 Psychological Bulletin, 133(1), 1-24. http://doi.org/10.1037/0033-2909.133.1.1
363 Becker, B., Mihov, Y., Scheele, D., Kendrick, K. M., Feinstein, J. S., Matusch, A., ... Hurlemann, R.
364 (2012). Fear processing and social networking in the absence of a functional amygdala. Biological
365 Psychiatry, 72(1), 70-7. http://doi.org/10.1016/j.biopsych.2011.11.024
366 Benuzzi, F., Meletti, S., Zamboni, G., Calandra-Buonaura, G., Serafini, M., Lui, F., ... Nichelli, P.
367 (2004). Impaired fear processing in right mesial temporal sclerosis: a fMRI study. Brain Research
368 Bulletin, 63(4), 269-81. http://doi.org/10.1016/j.brainresbull.2004.03.005
369 Birn, R. M., Shackman, a J., Oler, J. a, Williams, L. E., McFarlin, D. R., Rogers, G. M., ... Kalin, N. H.
370 (2014). Evolutionarily conserved prefrontal-amygdalar dysfunction in early-life anxiety. Molecular
371 Psychiatry, 19(8), 915-922. http://doi.org/10.1038/mp.2014.46
372 Bocanegra, B. R. (2014). Affecting speed and accuracy in perception. Cognitive, Affective & Behavioral
373 Neuroscience, 14(4), 1454-66. http://doi.org/10.3758/s13415-014-0296-5
374 Cisler, J. M., Bacon, A. K., & Williams, N. L. (2009). Phenomenological Characteristics of Attentional
375 Biases Towards Threat: A Critical Review. Cognitive Therapy and Research, 33(2), 221-234.
376 http://doi.org/10.1007/s 10608-007-9161-y
377 Cisler, J. M., & Koster, E. H. W. (2010). Mechanisms of attentional biases towards threat in anxiety
378 disorders: An integrative review. Clinical Psychology Review, 30(2), 203-16.
379 http://doi.org/10.1016/jxpr.2009.11.003
380 Corballis, M. C. (2009a). Comparing a single case with a control sample: Correction and further
381 comment. Neuropsychologia, 47(13), 2696-2697.
382 http://doi.org/10.10167j.neuropsychologia.2009.04.012
383 Corballis, M. C. (2009b). Comparing a single case with a control sample: Refinements and extensions.
384 Neuropsychologia, 47(13), 2687-2689. http://doi.org/10.1016/j.neuropsychologia.2009.04.007
385 Crawford, J. R., & Garthwaite, P. H. (2005). Testing for Suspected Impairments and Dissociations in
386 Single-Case Studies in Neuropsychology: Evaluation of Alternatives Using Monte Carlo
387 Simulations and Revised Tests for Dissociations. Neuropsychology, 19(3), 318-331.
388 http://doi.org/10.1037/0894-4105.19.3.318
389 Crawford, J. R., & Garthwaite, P. H. (2006). Methods of testing for a deficit in single-case studies:
390 Evaluation of statistical power by Monte Carlo simulation. Cognitive Neuropsychology, 23(6), 877391 904. http://doi.org/10.1080/02643290500538372
392 Crawford, J. R., & Garthwaite, P. H. (2012). Single-case research in neuropsychology: A comparison of
393 five forms of t-test for comparing a case to controls. Cortex, 48(8), 1009-1016.
394 http: //doi.org/ 10.1016/j. cortex. 2011.06.021
395 Crawford, J. R., Garthwaite, P. H., & Howell, D. C. (2009). On comparing a single case with a control
396 sample: An alternative perspective. Neuropsychologia, 47(13), 2690-2695.
397 http://doi.org/10.1016/j .neuropsychologia. 2009.04.011
398 Crawford, J. R., & Howell, D. C. (1998). Comparing an Individual's Test Score Against Norms Derived
399 from Small Samples. The Clinical Neuropsychologist (Neuropsychology, Development and
400 Cognition: Section D), 12(4), 482-486. http://doi.org/10.1076/clin. 12.4.482.7241
401 Creswell, C., Woolgar, M., Cooper, P., Giannakakis, A., Schofield, E., Young, A. W., & Murray, L.
402 (2008). Processing of faces and emotional expressions in infants at risk of social phobia. Cognition
403 & Emotion, 22(3), 437-458. http://doi.org/10.1080/02699930701872392
404 Dolan, R. J. (2002). Emotion, cognition, and behavior. Science (New York, N. Y.), 298(5596), 1191-4.
405 http://doi.org/10.1126/science. 1076358
406 Emsley, R. A., & Paster, L. (1985). Lipoid proteinosis presenting with neuropsychiatry manifestations.
407 Journal of Neurology, Neurosurgery & Psychiatry, 48(12), 1290-1292.
408 http://doi.org/10.1136/jnnp.48.12.1290
409 Feinstein, J. S., Adolphs, R., Damasio, A., & Tranel, D. (2011). The human amygdala and the induction
410 and experience of fear. Current Biology, 21(1), 34-38. http://doi.org/10.1016/jxub.2010.11.042
411 Field, A. P., & Lester, K. J. (2010). Is There Room for "Development" in Developmental Models of
412 Information Processing Biases to Threat in Children and Adolescents? Clinical Child and Family
413 Psychology Review, 13(4), 315-332. http://doi.org/10.1007/s10567-010-0078-8
414 Freese, J. L., & Amaral, D. G. (2009). Neuroanatomy of the Primate Amygdala. In P. J. Whalen & E. a.
415 Phelps (Eds.), The Human Amygdala (pp. 3-42). New York, NY, NY: Guilford Press.
416 Hakamata, Y., Lissek, S., Bar-Haim, Y., Britton, J. C., Fox, N. A., Leibenluft, E., ... Pine, D. S. (2010).
417 Attention bias modification treatment: A meta-analysis toward the establishment of novel treatment
418 for anxiety. Biological Psychiatry, 68(11), 982-990. http://doi.org/10.1016/j.biopsych.2010.07.021
419 Ito, D., Nagasaka, T., Tanaka, K., Osono, Y., Hirose, N., Koto, A., & Fukuuchi, Y. (2000). Hyalinosis
420 cutis et mucosae: a case report. Journal of Neurology, 247(1), 58-60.
421 http://doi.org/10.1007/s004150050012
422 Jacobs, R. H. a H., Renken, R., Aleman, A., & Cornelissen, F. W. (2012). The amygdala, top-down
423 effects, and selective attention to features. Neuroscience and Biobehavioral Reviews, 36(9), 2069424 84. http ://doi.org/10.1016/j.neubiorev.2012.05.011
425 Kennedy, D. P., & Adolphs, R. (2011). Reprint of: Impaired fixation to eyes following amygdala damage
426 arises from abnormal bottom-up attention. Neuropsychologia, 49(4), 589-595.
427 http://doi.org/10.1016/j.neuropsychologia.2011.02.026
428 Klein, R. M. (2000). Inhibition of return. Trends in Cognitive Sciences, 4(4), 138-147.
429 http://doi.org/10.1016/S1364-6613(00)01452-2
430 Koster, E. H. W., Crombez, G., Van Damme, S., Verschuere, B., & De Houwer, J. (2004). Does
431 imminent threat capture and hold attention? Emotion (Washington, D.C.), 4(3), 312-7.
432 http://doi.org/10.1037/1528-3542A3.312
433 Koster, E. H. W., Crombez, G., Verschuere, B., & De Houwer, J. (2004). Selective attention to threat in
434 the dot probe paradigm: differentiating vigilance and difficulty to disengage. Behaviour Research
435 and Therapy, 42(10), 1183-92. http://doi.org/10.1016/j.brat.2003.08.001
436 Koster, E. H. W., Verschuere, B., Crombez, G., & Van Damme, S. (2005). Time-course of attention for
437 threatening pictures in high and low trait anxiety. Behaviour Research and Therapy, 43(8), 1087-98.
438 http://doi.org/10.1016/j.brat.2004.08.004
439 Langner, O., Dotsch, R., Bijlstra, G., Wigboldus, D. H. J., Hawk, S. T., & van Knippenberg, A. (2010).
440 Presentation and validation of the Radboud Faces Database. Cognition & Emotion, 24(8), 1377441 1388. http://doi.org/10.1080/02699930903485076
442 LeDoux, J. (2007). The amygdala. Current Biology, 17(20), 868-874.
443 http://doi.org/10.1016/jxub.2007.08.005
444 Lindstrom, K. M., Guyer, A. E., Mogg, K., Bradley, B. P., Fox, N. A., Ernst, M., ... Bar-Haim, Y. (2009).
445 Normative data on development of neural and behavioral mechanisms underlying attention orienting
446 toward social-emotional stimuli: An exploratory study. Brain Research, 1292, 61-70.
447 http://doi.org/10.1016/j .brainres.2009.07.045
448 LoBue, V. (2009). More than just another face in the crowd: superior detection of threatening facial
449 expressions in children and adults. Developmental Science, 12(2), 305-313.
450 http://doi.org/10.1111/j.1467-7687.2008.00767.x
451 LoBue, V., & DeLoache, J. S. (2010). Superior detection of threat-relevant stimuli in infancy.
452 Developmental Science, 13(1), 221-228. http://doi.org/10.1111/j. 1467-7687.2009.00872.x
453 LoBue, V., & Rakison, D. H. (2013). What we fear most: A developmental advantage for threat-relevant
454 stimuli. Developmental Review, 33(4), 285-303. http://doi.org/10.1016/j.dr.2013.07.005
455 MacLeod, C., Mathews, A., & Tata, P. (1986). Attentional bias in emotional disorders. Journal of
456 Abnormal Psychology, 95(1), 15-20. http://doi.org/10.1037/0021-843X.95.1.15
457 Mcintosh, R. D., & Brooks, J. L. (2011). Current tests and trends in single-case neuropsychology. Cortex,
458 47(10), 1151-1159. http://doi.org/10.1016/jxortex.2011.08.005
459 Milham, M. P., Nugent, A. C., Drevets, W. C., Dickstein, D. S., Leibenluft, E., Ernst, M., ... Pine, D. S.
460 (2005). Selective reduction in amygdala volume in pediatric anxiety disorders: A voxel-based
461 morphometry investigation. Biological Psychiatry, 57(9), 961-966.
462 http://doi.org/10.1016/j .biopsych. 2005.01.038
463 Mogg, K., & Bradley, B. P. (1998). A cognitive-motivational analysis of anxiety. Behaviour Research
464 and Therapy, 36(9), 809-848. http://doi.org/10.1016/S0005-7967(98)00063-1
465 Ohman, A., & Mineka, S. (2001). Fears, phobias, and preparedness: Toward an evolved module of fear
466 and fear learning. Psychological Review, 108(3), 483-522. http://doi.org/10.1037/0033-
467 295X.108.3.483
468 Ollendick, T. H. (1983). Reliability and validity of the revised fear survey schedule for children (FSSC-
469 R). Behaviour Research and Therapy, 21(6), 685-692. http://doi.org/10.1016/0005-7967(83)90087-
471 Omrani, H. G., Tajdini, M., Ghelichnia, B., Hosseini, S. M. R., Tafakhori, A., Rahimian, E., &
472 Aghamollaii, V. (2012). Should we think of Urbach-Wiethe disease in refractory epilepsy? Case
473 report and review of the literature. Journal of the Neurological Sciences, 320(1-2), 149-52.
474 http://doi.org/10.1016/jjns.2012.06.019
475 Pessoa, L. (2009). How do emotion and motivation direct executive control? Trends in Cognitive
476 Sciences, 13(4), 160-6. http://doi.org/10.1016/j.tics.2009.01.006
477 Pessoa, L., & Adolphs, R. (2010). Emotion processing and the amygdala: from a "low road" to "many
478 roads" of evaluating biological significance. Nature Reviews Neuroscience, 11(11), 773-783.
479 http://doi.org/10.1038/nrn2920
480 Pessoa, L., Padmala, S., Kenzer, A., & Bauer, A. (2012). Interactions between cognition and emotion
481 during response inhibition. Emotion, 12, 192-197. http://doi.org/10.1037/a0024109
482 Phelps, E. a, Ling, S., & Carrasco, M. (2006). Emotion facilitates perception and potentiates the
483 perceptual benefits of attention. Psychological Science, 17(4), 292-9. http://doi.org/10.1111/j. 1467484 9280.2006.01701.x
485 Piech, R. M., McHugo, M., Smith, S. D., Dukic, M. S., Van Der Meer, J., Abou-Khalil, B., & Zald, D. H.
486 (2010). Fear-enhanced visual search persists after amygdala lesions. Neuropsychologia, 48(4),
487 3430-5. http://doi.org/10.1016/j.neuropsychologia.2011.02.029
488 Piech, R. M., McHugo, M., Smith, S. D., Dukic, M. S., Van Der Meer, J., Abou-Khalil, B., ... Zald, D. H.
489 (2011). Attentional capture by emotional stimuli is preserved in patients with amygdala lesions.
490 Neuropsychologia, 49(12), 3314-9. http://doi.org/10.1016/j.neuropsychologia.2011.08.004
491 Pourtois, G., Grandjean, D., Sander, D., & Vuilleumier, P. (2004). Electrophysiological correlates of
492 rapid spatial orienting towards fearful faces. Cerebral Cortex, 14(6), 619-633.
493 http://doi.org/10.1093/cercor/bhh023
494 Pourtois, G., Schettino, A., & Vuilleumier, P. (2013). Brain mechanisms for emotional influences on
495 perception and attention: what is magic and what is not. Biological Psychology, 92(3), 492-512.
496 http://doi.org/10.1016/j .biopsycho.2012.02.007
497 Pourtois, G., Schwartz, S., Seghier, M. L., Lazeyras, F., & Vuilleumier, P. (2006). Neural systems for
498 orienting attention to the location of threat signals: an event-related fMRI study. Neurolmage, 31(2),
499 920-33. http://doi.org/10.1016/j.neuroimage.2005.12.034
500 Pourtois, G., Thut, G., De Peralta, R. G., Michel, C., Vuilleumier, P., Grave de Peralta, R., ...
501 Vuilleumier, P. (2005). Two electrophysiological stages of spatial orienting towards fearful faces:
502 early temporo-parietal activation preceding gain control in extrastriate visual cortex. Neurolmage,
503 26(1), 149-163. http://doi.org/10.1016/j .neuroimage.2005.01.015
504 Rotshtein, P., Richardson, M. P., Winston, J. S., Kiebel, S. J., Vuilleumier, P., Eimer, M., ... Dolan, R. J.
505 (2010). Amygdala damage affects event-related potentials for fearful faces at specific time windows.
506 Human Brain Mapping, 31(7), 1089-105. http://doi.org/10.1002/hbm.20921
507 Salum, G. A., Mogg, K., Bradley, B. P., Gadelha, A., Pan, P., Tamanaha, A. C., ... Pine, D. S. (2013).
508 Threat bias in attention orienting: evidence of specificity in a large community-based study.
509 Psychological Medicine, 43(04), 733-745. http://doi.org/10.1017/S0033291712001651
510 Sander, D., Grafman, J., & Zalla, T. (2003). The human amygdala: an evolved system for relevance
511 detection. Reviews in the Neurosciences, 14(4), 303-316.
512 http://doi.org/10.1515/REVNEUR0.2003.14A303
513 Savage, M. M., Crockett, D. M., & McCabe, B. F. (1988). Lipoid proteinosis of the larynx: a cause of
514 voice change in the infant and young child. International Journal of Pediatric Otorhinolaryngology,
515 75(1), 33-38. http://doi.org/10.1016/0165-5876(88)90048-1
516 Schmolck, H., & Squire, L. R. (2001). Impaired perception of facial emotions following bilateral damage
517 to the anterior temporal lobe. Neuropsychology, 75(1), 30-38. http://doi.org/10.1037//0894-
518 4105.15.1.30
519 Schyns, P. G., Petro, L. S., & Smith, M. L. (2009). Transmission of facial expressions of emotion co-
520 evolved with their efficient decoding in the brain: behavioral and brain evidence. PloS One, 4(5),
521 e5625. http://doi.org/10.1371/journal.pone.0005625
522 Shechner, T., Britton, J. C., Pérez-Edgar, K., Bar-Haim, Y., Ernst, M., Fox, N. A., ... Pine, D. S. (2012).
523 Attention biases, anxiety, and development: toward or away from threats or rewards? Depression
524 and Anxiety, 29(4), 282-294. http://doi.org/10.1002/da.20914
525 Siebert, M., Markowitsch, H. J., & Bartel, P. (2003). Amygdala, affect and cognition: evidence from 10
526 patients with Urbach-Wiethe disease. Brain : A Journal of Neurology, 726(Pt 12), 2627-37.
527 http://doi.org/10.1093/brain/awg271
528 Smith, M. L., Cottrell, G. W., Gosselin, F., & Schyns, P. G. (2005). Transmitting and decoding facial
529 expressions. Psychological Science, 76(3), 184-9. http://doi.org/10.1111/j.0956-7976.2005.00801.x
530 Sprengelmeyer, R., Young, a W., Schroeder, U., Grossenbacher, P. G., Federlein, J., Büttner, T., &
531 Przuntek, H. (1999). Knowing no fear. Proceedings. Biological Sciences / The Royal Society,
532 266(1437), 2451-6. http://doi.org/10.1098/rspb.1999.0945
533 Steenberg, E. (2014). The neuropsychological and psychosocial functioning of children and adolescents
534 with Lipoid Proteinosis. University of the Free State. Retrieved from http://etd.uovs.ac.za/ETD-
535 db/theses/available/etd-08072014-16123 0/unrestricted/SteenbergE.pdf
536 Swanson, L. W., & Petrovich, G. D. (1998). What is the amygdala? Trends in Neurosciences, 27(8), 323537 331. http://doi.org/10.1016/S0166-2236(98)01265-X
538 Terburg, D., Morgan, B. E., Montoya, E. R., Hooge, I. T., Thornton, H. B., Hariri, a R., ... van Honk, J.
539 (2012). Hypervigilance for fear after basolateral amygdala damage in humans. Translational
540 Psychiatry, 2(5), e115. http://doi.org/10.1038/tp.2012.46
541 Thornton, H. B., Nel, D., Thornton, D., van Honk, J., Baker, G. A., & Stein, D. J. (2008). The
542 Neuropsychiatry and Neuropsychology Of Lipoid Proteinosis. Journal of Neuropsychiatry, 20(1),
543 86-92. http://doi.org/10.1176/appi.neuropsych.20.1.86
544 Tranel, D., Gullickson, G., Koch, M., & Adolphs, R. (2006). Altered experience of emotion following
545 bilateral amygdala damage. Cognitive Neuropsychiatry, 77(3), 219-232.
546 http://doi.org/10.1080/13546800444000281
547 Tsuchiya, N., Moradi, F., Felsen, C., Yamazaki, M., & Adolphs, R. (2009). Intact rapid detection of
548 fearful faces in the absence of the amygdala. Nature Neuroscience, 72(10), 1224-5.
549 http://doi.org/10.1038/nn.2380
550 Vuilleumier, P. (2005). How brains beware: Neural mechanisms of emotional attention. Trends in
551 Cognitive Sciences. http://doi.org/10.1016/j.tics.2005.10.011
552 Vuilleumier, P., Richardson, M. P., Armony, J. L., Driver, J., & Dolan, R. J. (2004). Distant influences of
553 amygdala lesion on visual cortical activation during emotional face processing. Nature
554 Neuroscience, 7(11), 1271-8. http://doi.org/10.1038/nn1341
555 Waters, A. M., Lipp, O. V., & Spence, S. H. (2004). Attentional bias toward fear-related stimuli: Journal
556 of Experimental Child Psychology, 89(4), 320-337. http://doi.org/10.1016/jjecp.2004.06.003
557 Wolters, L. H., de Haan, E., Vervoort, L., Hogendoorn, S. M., Boer, F., & Prins, P. J. M. (2012). The
558 time-course of threat processing in children: a temporal dissociation between selective attention and
559 behavioral interference. Anxiety, Stress & Coping, 25(3), 259-273.
560 http://doi.org/10.1080/10615806.2011.581278
561 Yiend, J. (2010). The effects of emotion on attention: A review of attentional processing of emotional
562 information. Cognition & Emotion, 24(1), 3-47. http://doi.org/10.1080/02699930903205698
564 Figure Legends
565 Figure 1. T1, T2, and FLAIR sequence MRI of SF. Images demonstrate bilateral amygdala lesions
566 (arrowheads) as a result of symmetrical calcifications due to Urbach-Wiethe disease. Each column
567 presents corresponding axial sections; from left to right at 24, 18, and 12 millimiters below the anterior
568 commissure. Images are in radiological convention.
569 Figure 2. Stimuli sequence, experimental conditions, and alternative results of the dot-probe task.
570 (A) Each trial started with a fixation cross. Each cue display consisted of a pair of face image of the same
571 identity. On neutral trials (right), the same face with a neutral expression was displayed on both sides. In
572 the other two conditions, one of the two faces was fearful. In congruent trials (left), the target appeared on
573 the same side as the fearful face. In incongruent trials (middle) the target appeared on the opposite
574 hemifield. Three cue durations (100, 500, and 1000ms) occurred with equal probability. Stimuli are not
575 drawn to scale. (B) Schematics of typical behavioral results obtained in dot-probe tasks. Significant
576 difference between reaction times (RT) in congruent and incongruent trials indicates an attentional bias
577 towards (left and middle panels) or away (right panel) from fear. A positive congruency effect could be
578 due to either 'facilitated engagement' (left) or 'difficulty in disengagement' (right). Comparison with
579 baseline (RT in neutral trials; horizontal black lines) is necessary to determine the affected components of
580 attentional bias.
581 Figure 3. Deficits in experiential emotion processing with developmental amygdala damage. (A)
582 Participants' scores from the Fear Survey Schedule for Children-Revised (FSSC-R). SF had a
583 significantly lower score, suggesting that she had lower everyday experience of fear. (B) Performance
584 accuracy in the facial expression classification task. SF was specifically impaired in classifying the fearful
585 facial expression. (C) Distribution of labels assigned to fearful faces. SF assigned the 'surprised' label to
586 69% of the fearful faces.
587 Figure 4. Results of the dot-probe task. Panel (A) shows the attentional bias scores of SF and controls
588 at each cue exposure duration. Bias score is calculated by subtracting reaction times on congruent trials
589 from reaction times on incongruent trials. Positive attentional bias scores indicate attention towards the
590 fearful face. Negative scores indicate avoidance of fear location. Panels (B-G) show mean reaction time
591 of SF and controls on congruent, incongruent, and neutral trials at each cue exposure duration. SF showed
592 attentional bias towards fearful faces mediated by facilitated engagement effect at 100ms (B); generally
593 slower reaction times in trials including a fearful face, but no significant attentional bias at 500ms (C);
594 and bias to avoid the location of fearful faces, probably due to inhibition of return at the exposure
595 duration of 1000ms (D). Controls showed a trend to avoid fearful faces at 100ms (E); significant
596 attentional bias was observed afterwards at 500ms (F); and at 1000ms mediated by difficulty to disengage
597 from the location of fearful faces (G). Horizontal black lines indicate the mean reaction time at neutral
598 trials. Dotted lines represent significant difference with baseline. Error bars show ±standard error of
599 mean, representing within-subject variance in SF (uncapped bars) and between-subject variance in
600 controls (capped bars). * p <0.05, ** p <0.01
Z = -24
Z = -18
Z = -12
Target
till response or 2000 ms
100, 500 or 1000 ms
Fixation
1000 ms
Congruent
Incongruent
Neutral
Positive congruency effect (Vigilance)
Facilitated engagement Difficulty in disengagement
[RTcongruent < RTincongruent]
Incongruent Congruent
[RTincongruent > RTneutral.
Incongruent Congruent
Negative congruency effect (Avoidance)
[RTcongruent > RTincongruent]
[RTincongruent < RTneutral.
Incongruent Congruent
co o Vi co m _co
□ SF ♦ Controls
100%-80%" 60%" 40%-20% 0%
angry disgusted fearful happy Facial expression
<D 80%-
co 60%"
40% 20% 0%
angry disgusted fearful happy
sad surprised
sad surprised
Label chosen in response to fearful faces
Cue duration
^_) 690-
s—( 670-
c 650-
"-4—'
o co 630-
C co 610-
"-4—'
100 ms
500 ms
1000 ms
'(B) : '(C) 1 ** '(D)
(E ) (F ) '(G) xr<4
Trial type
Incongruent Congruent Incongruent Congruent Incongruent Congruent
